Process for preparing isomaltol



United States Patent Oflfice 3,054,805 Patented Sept. 18, 1962 3,054,805PROCESS FOR PREPARING ISOMALTOL John E. Hodge and Earl C. Nelson,Peoria, 11]., assignors to the United States of America as representedby the Secretary of Agriculture No Drawing. Original application Dec.10, 1959, Ser. No. 858,837, now Patent No. 3,015,654, dated Jan. 2,1962. Divided and this application Aug. 16, 1961,

Ser. No. 131,940

2 Claims. (Cl. 260-3453) (Granted under Title 35, US. Code (1952), sec.266) A nonexclusive, irrevocable, royalty-free license in the inventionherein described, throughout the world for all purposes of the UnitedStates Government, with the power to grant sublicenses for suchpurposes, is hereby granted to the Government of the United States ofAmerica.

This is a division of applicants copending application, S.N. 858,837,filed December 10, 1959, now Patent No. 3,015,654.

This invention pertains to a method for preparing the known compound,isomaltol (Backe: Comptes Rendus 150: 540543 (1910) and ibid 151: 78-80(1910)).

This invention further relates to the preparation of a new compound,O-galactosylisomaltol.

Maltol, discovered by Brand in roasted malt, is commercially available.It has a marked caramel-butterscotch aroma and flavor and accordingly isemployed in confectionary products, pastries and related bakeryproducts, fruit flavors, and in other foodstuffs where a caramellike andfruity flavor is desired.

Isomaltol was discovered by Backe, supra, who obtained it in microquantities by acidic extractive distillation of breads made of wheatflour. It possesses a caramel-like, somewhat fruity flavor very similarto that of maltol. However, it melts at 102 C. rather than at 162 C. andis considerably more volatile than maltol. Accordingly, it would bepreferred for many applications if it became available at a comparableprice.

Our novel compound, O-galactosylisomaltol, is an O- glycoside in whichD-galactose is linked to the isomaltol aglycone through the stronglyacidic enolic hydroxyl group of the latter. We believe thatO-galactosylisomaltol has the following structure:

OCtHn05 l (galactosyl) HC-C H "i HO C-C-CHa Our new method or processfor the preparation of isomalto-l in favorable yields involves thediscovery that we can synthesize the novel intermediate compound 0-galactosylisomaltol, which readily hydrolyzes in the presence of acid oralkali or under the influence of heat and moisture to liberate isomaltoland galactose. It is obvious that it would not be necessary to split theO-galactosylisomaltol and isolate the isomaltol for flavor use inpastries, baked goods, boiled candies, etc. (and especially thosecontaining a hydrolysis-promoting acid such as citric or tartaric) sincethe galactoside is hydrolyzed to the flavorful isomaltol and theharmless galactose by the heat and steam present during the cooking orbaking process.

Our invention comprises the discovery that we can synthesize our novelintermediate, namely O-galactosylisomaltol by reacting milk sugar, suchas a-lactose hydrate or other source of lactose, with the salt of astrongly basic secondary amine (K in water) such as piperidine acetate,piperidine dihydrogen phosphate, morpholine acetate, dimethylamineacetate, diethylamine formate,

or diethanolamine phosphate in an inert solvent medium such as methanol,ethanol, isopropan'ol, or dimethylformamide, and in the further presenceof a non-reactant tertiary amine buffer such as trimethylamine,triethylamine, triethanolamine, N-methylmorpholine, pyridine, and mixedpyridine bases (isomeric picolines) or a sterically hinderednon-reactant secondary amine such as di-isopropylamine,dicyclohexylamine, and 2,6-dimethylpiperidine at a reaction temperaturein the range 60 to 100 C. for from 10 to 24 hours. At the end of thereaction period O-galactosylisomaltol is crystallized and recovered fromthe reaction mixture by filtration.

Isolation of the O-galactosylisomaltoi would not be necessary in acommercial process for preparing isomaltol. As is shown by the examples,the reaction mixture can be acidified and then steam distilled oracidified, heated, and solvent-extracted with benzene, chlorinatedhydrocarbons, ethers, esters, ketones, hydrocarbons, or higher alcoholsto obtain the isomaltol by evaporation of the solvent.

The amine salt reactant of our invention is basic, neutral, or weaklyacidic; it is not strongly acidic. Because it can be recovered from thereaction mixture unchanged, it acts in a catalytic manner and thereforethe amount used is not critical. However, we prefer to use from onehalfto two moles of amine salt for each mole of lactose in the reactionmixture to obtain reasonable reaction times in the temperature range of60 to 100 C. We need not add amine salt as such to the reaction mixture;ordinarily we add the basic secondary amine and the salt-forming acidseparately in the desired ratio. Furthermore, because organic acids aregenerated as byproducts in the reaction mixture as the desired reactionproceeds, it is not necessary to add a full mole of the salt-formingacid for each mole of secondary amine reactant.

The inert solvent is not necessary for the synthesis ofO-galactosylisomaltol. We have conducted the reaction in non-reactanttertiary amine media without the addition of further solvent. However,use of an alcoholic solvent allows cleaner and easier separation ofO-galactosylisomaltol from byproducts in the reaction mixture and allowsthe selection and fixing of a nearly constant reaction temperature byboiling and refluxing the properly selected solvent.

The presence of non-reactant tertiary amine or nonreactant stericallyhindered secondary amine is not necessary for the synthesis ofO-galactosylisomaltol. We have conducted the synthesis successfully inalcoholic media and in dimethylformamide without the use of nonreactantamine buffer. However, when it is desired to recoverO-galactosylisomal-tol, we prefer to add to the reaction mixture anamount of tertiary amine or nonreactant secondary amine that will keepthe reaction mixture weakly basic throughout the heating period tothereby prevent hydrolysis and loss of O-gal-actosylisom-altol. When itis desired to recover isomaltol from the reaction mixture, for example,by acidification and steam distillation, the amine buffer need not beused.

An O-glucosylisornaltol was not found using maltose hydrate in place ofa-l-actose hydrate under the conditions outlined in the examples, but itis apparent that B-lactose hydrate, anhydrous ,B-lactose, anhydroustit-lactose, and other sources of lactose such as dried whey and ,driedskim milk would be operative.

The following examples are presented to further teach the practice ofour invention.

Example 1 In a 2-liter, 3-necked reaction flask, fitted with amotordriven anchor-bladed stirrer, thermometer, and reflux condenser,360 g. (1 mole) of tit-lactose hydrate, g. (1 mole) of piperidine, 60 g.(1 mole) of glacial acetic acid,

product was present and was isolated in 28 percent of the theoreticalyield in a separate experiment. After 24 hours of heating at 75 C., 300ml. of absolute ethanol was 'added; then the dark brown reaction mixturewas continuallystirred for one hour While the flask was cooled in anice-water bath to crystallize the product. The precipitate was filteredoff with suction, washed several times with ethanol until nearly white,and dried in a vacuum desiccator over anhydrous calcium chloride to aconstant weight of 106 g. (37 percent of theory); melting point, 204-205C. Recrystallization from hot water or aqueous alcohol with the use ofdecolorizing charcoal gave pure white crystals of the same meltingpoint, and with a specific optical rotation of 4.5 for a 2 percentsolution in water with sodium light. Analyses gave 50.18 percent carbon,5.65 percent hydrogen. Calculated for C H O 50.00 percent carbon, 5.60percent hydrogen.

Acid hydrolysis or acid hydrogenolysis of the neutral compound, C H Ogave crystalline m-D-galactose, C l-1 M.P. 16Sl67, identified by itsoptical rotation in water and by its conversion by nitric acid tocrystalline mucic acid, M.P. 213-214. Methanolysis in anhydrousmethanol-hydrogen chloride gave the known methyl fl-D-galactopyranoside,0 1-1 0 M.P. 177-178, no optical rotation in water; found: 43.30 percentcarbon, 7.33 percent hydrogen. Calculated for C7H14O6 43.30 percentcarbon, 7.28 percent hydrogen.

When the acid hydrolysate of the neutral compound, C H O was extractedwith ether and the ether extracts concentrated by evaporation, acolorless acidic compound was crystallized. Recrystallized and sublimed,the acidic compound melted at IOU-101 C. By titration with standardbase, the neutral equivalent was 124. Found: 57.18 percent carbon, 4.80percent hydrogen. Calculated for C H O 126.1 molecular weight, 57.14percent carbon, 4.80 percent hydrogen. This same compound was sublimedand distilled from the neutral C H O compound when it was heated to 205and caramelized. It was identified as isomaltol, by converting it to theO-methyl ether (M.P. 101-103), the O-benzoyl ester (M.P. 100-10l), andthe same green copper salt reported in the literature. Moreover, thestable violet color with ferric chloride, the acidity, the volatility,the solubilities, and the reducing action toward Fehling solutionconformed exactly to the literature reports.

Example 2 In the same apparatus described in Example 1, precooled to 1C., the following were added in the order given: 500 ml. absolutemethanol, 48 g. (1.06 moles) of anhydrous dimethylamine, 100 g.trimethylamine, 360 g. (1.00 mole) of a-lactose hydrate, and 60 g. (1.00mole) of glacial acetic acid was slowly dropped in with stirring. Themixture was then continually stirred and heated under reflux at itsboiling point for 24 hours. The temperature increased from 60 (1 hour)to 67 (2 hours) to 68 hours) to 71 (20 hours) and to 72 C. at 24 hours.The reaction flask was cooled to 2 C. and held at this temperature forone hour until crystallization of the product was essentially complete.Isolated as described in Example 1, this first crop weighed 60.5 g.

The filtrate and washings were reheated at a constant reflux temperatureof 77:1 C. for 8 hours. After removing the solvents by distillation atatmospheric pressure over 2 additional hours, the dark solution wasagain cooled to 1 C. and a second crop, isolated in the same way as thefirst, weighed 3 g.

Both crops were identical, M.P. 204-205 representing the same compound,C I-1 0 as was obtained in Example 1. The total yield in this experimentwas 63.5 g., 22 percent of the theoretical amount.

4 Example 3 The reaction described in Example 1 was repeated with 87 g.of morpholine (1 mole) in place of g. of piperidine, except that thereaction mixture was refluxed at its natural boiling point of 82 C. for24 hours. The same compound, O-galactosylisomaltol, C H -O was isolated,59.2 g. (21 percent of theory). The filtrate from the reaction mixturewas reheated at the boiling point, 82-83, for 24 hours longer to produce15.4 g. additional O-galactosylisomaltol. Total yield, 74.6 g. (26percent of theory).

Example 4 Tlhirteen grams of crude O galactosylisomaltol,

CIZHIGOS was suspended in ml. of water and 100 ml. of 4-molarorthophosphoric acid was added. The 2-molar acidic solution wassteam-distilled until 900 ml. of aqueous distillate was collected, and aviolet color was no longer ob tained from drops of the distillate uponaddition of ferric chloride. The distillate was extracted three timeswith 200 ml. portions of chloroform. The chloroform layers wereseparated, combined, dried over anhydrous sodium sulfate, and thendistilled at atmospheric pressure. The crystalline residue in thedistilling flask was washed out with cold water and dried in air to aconstant weight of 2.3 g. (40 percent of the theoretical amount ofisomaltol from 13 g. of O-galactosylisomaltol). When purified byrecrystallization from benzene, the compound was identical in allproperties with the isomaltol isolated by ether extraction of an acidhydrolysate of O-galactosylisomaltol (Example 1).

Example 5 Forty grams of O-galactosylisomaltol, C H O was placed in a250 ml. alembic flask which was then lowered into a Woods metal bathpreheated to 230 C. Distillation began with liquefaction andcaramelization of the O-galactosylisomaltol within 3 minutes andcontinued at atmospheric pressure for 10 minutes as the bath temperaturewas held in the range 245-260 C. The liquid distillate of strong,fragrant aromatic odor, immediately crystallized in the receiver. Yield,14 g. The crystalline distillate was broken up under Water at roomtemperature and cooled to 1 C. before filtering and re-washing withice-water. After drying over anhydrous calcium chloride at atmosphericpressure, the yield of pure compound was 12 g. (68 percent of theory);M.P. 101-102, unchanged upon recrystallization from water or ether. Thiscompound was identical with isomaltol obtained in Example 1.

Example 6 Anhydrous dimethylamine, 23 g. (0.5 mole), was dissolved in300 ml. of dimethylformamide, and g. (0.5 mole) of a-lactose hydrate wasadded. While cooling the mixture at 0 C., 30 g. (0.5 mole) of glacialacetic acid was slowly added; then the mixture was heated at 90 C. underreflux for 12 hours. After concentration of the dark solution undervacuum at 90, 18-20 mm. mercury pressure, for 3 hours to remove most ofthe solvent, the warm sirupy residue was diluted with 300 ml. of hot,absolute ethanol. A small amount of insoluble, dark, crnelanoidin-likesubstance was filtered off. The filtrate, upon cooling and seeding, gave14 g.'; and, after vacuum concentration of the second filtrate, 12 g.more of O-galactosylisomaltol, M.P. 204-5 The total yield is 18 percentof the theoretical amount.

Example 7 combined ether extracts were dried over anhydrous sodiumsulfate and distilled to yield 1 g. of crystalline isomaltol (25 percentof theory); M.P. 99-101".

Example 8 A pie crust dough consisting of 62.5 gm. flour, 36. gm.hydrogenated vegetable oil shortening, 15 ml. cold water, and 0.3125 gm.O-galactosylisomaltol (0.5 percent based on the Weight of the flour) wasrolled to a thickness of A3 inch and baked for 8 minutes at 500 F. Ataste panel preferred this pie crust over one identically preparedexcept that it did not contain O-galactosylisomaltol.

Having disclosed our invention, we claim:

1. The method of recovering pure isomaltol comprising pyrolyzingO-galactosylisomaltol at a temperature of about from 245260 C. in theabsence of added moisture to liberate isomaltol, and recovering theisomaltol.

2. The method of recovering pure isomaltol comprising subjectingO-ga-lactosylisomaltol to alkali hydrolysis to liberate isomaltol,extracting the isomaltol With an organic solvent, and recovering pureisomaltol from the resulting 1D extract.

No references cited.

1. THE METHOD OF RECOVERING PURE ISOMALTOL COMPRISING PYROLYZINGO-GALACTOSYLISOMALTOL AT A TEMPERATURE OF ABOUT FROM 245-260*C. IN THEABSENCE OF ADDED MOISTURE TO LIBERATE ISOMALTOL, AND RECOVERILNG THEISOMALTOL.